Synthesis of the trichloroacetamide derivative of enantio-iso-ADDA methyl ester

Article abstract of DOI:10.1016/j.tet.2009.02.004

The divergent syntheses of the trichloroacetamide derivatives of (2S,3R,8R,9R,4E,6E)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-decadenoic acid (enantio-iso-ADDA), and (2R,3R,8R,9R,4E,6E)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-decadenoic acid (enant

Full text of DOI:10.1016/j.tet.2009.02.004

Tetrahedron 65 (2009) 2951–2958
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of the trichloroacetamide derivative of enantio-iso-ADDA methyl ester
,
y
*
Sebastien Meiries, Andrew Parkin, Rodolfo Marquez
WestChem Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, Scotland, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The divergent syntheses of the trichloroacetamide derivatives of (2S,3R,8R,9R,4E,6E)-3-amino-9-
methoxy-2,6,8-trimethyl-10-phenyl-decadenoic acid (enantio-iso-ADDA), and (2R,3R,8R,9R,4E,6E)-3-
amino-9-methoxy-2,6,8-trimethyl-10-phenyl-decadenoic acid (enantio-ADDA), have been achieved. Our
approach takes advantage of highly efficient non-aldol aldol, palladium catalysed aza-Claisen and cross-
metathesis methodologies.
Received 16 October 2008
Received in revised form 15 January 2009
Accepted 5 February 2009
Available online 11 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated to the memory of our esteemed
colleague Dr. Andy Parkin
Keywords:
ADDA
iso-ADDA
Phosphatase
iso-Motuporin
1. Introduction
abolishes the PP inhibitory activity of the microcystins, nodularin
and motuporin.
iso-Motuporin 1 is a macrocyclic peptide isolated recently from
the marine sponge Theonella swinhoei.1 iso-Motuporin is closely
related to motuporin 2, nodularin 3 and the microcystins 4. The key
Interestingly, naturally occurring 6Z-ADDA nodularin and
microcystin analogues display none of the toxicity associated with
the parent compounds.6
structural difference between them is that the unusual
b
-amino
The unique structure of ADDA as well as its biological relevance
has inspired a number of synthetic approaches developed to date.7
Reports by Chamberlin and co-workers have demonstrated that
microcystin analogues 6 incorporating the N-acylated ADDA chain
and a single amino acid retain moderate activity as PP1/PP2A
inhibitors (Fig. 2).8,9 The recent discovery of iso-motuporin has not
allowed any of these studies to be carried out with either iso-
motuporin 1 or iso-ADDA 7.
All this evidence suggests that stereoisomeric forms of the
ADDA scaffold (and conversely peptides incorporating them) might
provide an alternative starting point for the development of novel
biological chemistry probes to study and dissect phosphatase
activity.
acid unit (2S,3S,8S,9S,4E,6E)-3-amino-9-methoxy-2,6,8-trimethyl-
10-phenyl-decadenoic acid ‘ADDA’ present in the microcystins,
nodularin and motuporin has been mutated into the isomeric
b
-amino acid unit (2R,3S,8S,9S,4E,6E)-3-amino-9-methoxy-2,6,8-
trimethyl-10-phenyl-decadenoic acid ‘iso-ADDA’ (Fig. 1).
Biologically, the microcystins, nodularin and motuporin exhibit
significant activity as protein phosphatase inhibitors.2 Protein
phosphatases (PPs) are key proteins with significant roles in signal
transduction pathways, and are involved in a variety of processes
including cell division, neurotransmission, memory and learning.3
However, the understanding of the relative pharmacological
functions of the various phosphatase families remains fairly lim-
ited due to their structural similarities and the lack of selective
inhibitors.4
2. Results and discussion
Unfortunately, the high toxicity of the microcystins, nodularin
and motuporin has kept them from being developed as potential
therapeutic leads.5 Importantly, truncation of the ADDA chain
As part of our efforts towards the generation of novel ADDA
isoforms that might help expand our knowledge of this important
subunit, we would like to report the first total synthesis of fully
protected enantio-iso-ADDA. An efficient total synthesis of enantio-
iso-ADDA would allow us to compare its biological and physical
properties to those of enantio-ADDA (recently synthesised by our
group) and to evaluate its biological activity both on its own, and
* Corresponding author. Tel.: þ44 0141 330 5953; fax: þ44 0141 330 488.
E-mail address: r.marquez@chem.gla.ac.uk (R. Marquez).
y
Ian Sword Lecturer of Organic Chemistry.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.004

2952
S. Meiries et al. / Tetrahedron 65 (2009) 2951–2958
O
CO2H
O
NMe
NH
OMe
N
H
NH
OMe
HN
CCl3
CO2R'
O
O
H
N
O
8
O
1
O
CO2H
OMe
9
HN
CCl3
CO2R'
O
CO2H
NMe
OMe
N
H
10
O
O
NH
H
N
NH
O
NH
OTBS
2
O
CO2H
CHO
Cl3C
O
OR
O
CO2H
12
11
NMe
Scheme 1.
OMe
N
H
O
O
NH
Our synthesis of the right hand unit began with the commer-
cially available methyl (R)-(ꢀ)-3-hydroxy-2-methylpropionate 13,
which was protected as the trityl ether 14 in quantitative yield.
Lithium aluminium hydride reduction of the ester unit, then gen-
erated the mono-protected 1,3-diol 15 in high yield and with no
epimerisation being observed (Scheme 2).
H
N
NH
O
O
CO2H
3
NH
H2N
N
H
CO2H
O
O
Me
N
HN
NH
LiAlH4
67%
TrCl, TEA
100%
MeO2C
MeO2C
OH
OTr
O
OMe
O
13
14
NH
HN
i) Swern Oxidation
ii) PPh3CHCO2Me
H
N
H
N
O
MeO2C
HO
OTr
OTr
O
4
90%
O
CO2H
16
15
Figure 1. iso-Motuporin 1, motuporin 2, nodularin 3 and microcystin LA 4.
Dibal-H
78%
Cl3CCN, DBU
97%
HO
OTr
17
NH
PdCl2(CN)2, p-
NHCOCCl3
OTr
OMe
NH2
benzoquinone
Cl3C
O
OTr
CO2H
89%
18
19 (4:1) syn:anti
5
6
7
OMe
NH2
O
CO2H
One-pot: Cl3CCN, DBU, then
PdCl2(CN)2, p-benzoquinone
HO
OTr
N
H
17
95%
Scheme 2.
OMe
NH2
CO2H
Swern oxidation of alcohol 15 followed by a Wittig olefination of
the aldehyde intermediate afforded the desired conjugated ester 16
as a single double bond isomer in excellent yield and with no
detectable epimerisation over the two-step sequence.
Figure 2. ADDA 5, ADDA analogue 6 and iso-ADDA 7.
A selective 1,2-reduction of conjugated ester 16 then afforded
the desired allylic alcohol 17 in good yield. Treatment of alcohol 17
with trichloroacetonitrile then gave the expected trichloroace-
timidate intermediate 18 in nearly quantitative yield.
when attached to naturally occurring macrocyclic peptides and
known pharmacophores.
Retrosynthetically, we envisioned enantio-iso-ADDA 8 as having
originated through the convergent cross-metathesis coupling of
the previously generated diene 9 with allylic amine 10. Our con-
vergent approach relies on the highly effective E,E-selective diene
cross-metathesis, which has been utilised by Koide, Crimmins, and
most recently by us.10 As per our previous work, diene 9 could be
readily secured through the olefination of aldehyde 11, in turn
easily accessible through Jung’s non-aldol aldol methodology.11 The
allylic amide-coupling partner 10 on the other hand was envisioned
as having originated through the Overman palladium catalysed
rearrangement of trichloroacetimidate 12 (Scheme 1).12
Treatment of the newly obtained trichloroacetimidate 18 under
Overman’s palladium(II) mediated aza-Claisen conditions pro-
ceeded to generate the expected allylic amide unit 19 in high yield
and as a 4:1 mixture of syn/anti diastereomers.12 Significantly,
a novel one-pot trichloroacetamidate generation and aza-Claisen
rearrangement further improved the overall transformation yield
(95% from alcohol 17) with similar diastereomeric ratios. The two
diastereomers could be successfully separated through a selective
recrystallisation of the major diasteromer 19syn, which corrobo-
rated the absolute stereochemistry of the amido-ether in-
termediate (Fig. 3).13

S. Meiries et al. / Tetrahedron 65 (2009) 2951–2958
2953
i) Pinnick Ox.
ii) CH2N2
NHCOCCl3
CO2Me
NHCOCCl3
CHO
Swern Ox.
20
EtNiPr2
69%
from 20
22
25
Scheme 4.
Interestingly, when the single diastereomer 22 was treated with
TMSOK in THF, a significant amount of epimerisation was observed
as well as partial decomposition (Scheme 5). This isomerisation
raises the possibility that iso-motuporin might be the product of
the biological isomerisation of motuporin rather than being
produced through a different metabolic pathway entirely.
NHCOCCl3
CO2Me
NHCOCCl3
CO2Me
NHCOCCl3
CO2Me
Figure 3. Crystal structure of allylic amine 19syn.
TMSOK
+
Δ, 24h
(1:1)
Treatment of trityl intermediate 19syn with an etheral HCl
solution proceeded to generate the desired primary alcohol 20,
which upon a sequential Swern–Pinnick oxidation procedure
afforded the desired amido-acid intermediate 21 in excellent yield
over the three-step process (Scheme 3). Interestingly, the use of
triethylamine as part of the Swern procedure resulted in significant
epimerisation of the aldehyde intermediate, which translated into
the generation of an inseparable 5:3 mixture of syn/anti di-
astereomers.14 Methylation of the carboxylic acid mixture using
TMS-diazomethane in diethyl ether produced the syn and anti
methyl esters 22 and 23 (5:3 ratio of diastereomers) as well as the
TMS-methylene esters 24. Separation by reverse phase semi-
preparative HPLC allowed the isolation of esters 22, 23 and the
enriched TMS ester 24syn.
22
22
23
Scheme 5.
Having successfully achieved the synthesis of the amido ester
unit 22, the key cross-metathesis was attempted with diene 9 using
our previously developed conditions.
We are pleased to report that treatment of diene 9 with allylic
amides 22 and 23 (both as single components and as a mixture of
diastereomers) in the presence of second generation Hoveyda–
Grubbs catalyst 26 in THF generated the fully protected enantio-iso-
ADDA and enantio-ADDA derivatives reproducibly in excellent
yields and as single E,E diastereomers (Scheme 6). The cross-cou-
pling, however, was found to be highly susceptible to the solvent
used, and the yield dropped to 20% when the coupling was
attempted in toluene.
NHCOCCl3
OH
NHCOCCl3
OTr
O
HCl, Et2O
100%
OMe
OMe
HN
HN
CCl3
CO2Me
19syn
20
26
OMe
(7% mol),
22 and/or 23
NHCOCCl3
i) Swern oxidation
27
ii) Pinnick oxidation
96%
TMSCHN2
69%
CO2H
90%
Ph
O
and/or
9
21 (5:3) (syn:anti)
CCl3
CO2Me
NHCOCCl3
NHCOCCl3
NHCOCCl3
N
N
CO2Me
CO2Me
+
+
CO2CH2TMS
28
Cl
Ru
Cl
26
22
5:3 (27%)
23
24 (42%)
O
Scheme 3.
Scheme 6.
Although unexpected, the epimerisation observed during the
triethylamine based Swern oxidation to generate the anti allylic
amine unit 23 was a welcome result. This epimerization effectively
allowed the generation of the non-trivial to generate anti allylic
amide using these steps. Interestingly, all attempts to exclusively
obtain the anti allylic amine through thermal conditions failed to
yield any rearrangement products.
Conversely, treatment of alcohol 20 under a Hunig’s base
derived Swern oxidation gave the aldehyde intermediate 25 with
no observable epimerisation.14 The crude aldehyde 25 was then
converted to the diastereomerically pure methyl ester 22 through
a Pinnick oxidation–diazomethane methylation sequence. Diazo-
methane provided a much cleaner methylation and in a higher
yield than that performed with TMS-diazomethane. It should also
be noted that Dess–Martin periodinane was also successful at
avoiding epimerisation, however, required extensive purification to
generate the clean methyl ester 22 (Scheme 4).14
It is important to highlight that in the case where the di-
astereomeric mixture was used in this coupling step, the products
proved impossible to separate even through the use of HPLC
methods. Furthermore, the spectroscopic and optical rotation data
24
of both diastereomers were very similar to each other ([
a
]
D
þ12.4
24
for 27, and [
a]
þ11.2 for 28) demonstrating the difficulty in sep-
D
arating, and identifying correctly different isoforms of the ADDA
unit.
In conclusion, we have completed the first synthesis of fully
protected enantio-iso-ADDA 27 as well as that of enantio-ADDA 28
utilising non-aldol aldol, palladium catalysed rearrangements
and cross-metathesis methodologies to introduce the key
functionalities.
Our convergent approach can be easily scaled up and allows for
the generation of key ADDA isoforms, enantio-iso-ADDA and
enantio-ADDA, taking advantage of an effective isomerisation

2954
S. Meiries et al. / Tetrahedron 65 (2009) 2951–2958
during the synthesis of the allylic amine coupling partner.
Furthermore the methodology and procedures used as part of our
syntheses allow for the rapid generation of all ADDA isoforms
through the simple modification of the Jung non-aldol aldol rear-
rangement precursor, and through the use of the desired starting
propionate.
on crude in the next reaction without any purification. The spec-
troscopic data was in full agreement with that reported in the
25
23
literature. [
a
]
D
ꢀ19.7 (c 1.0, CHCl3) compared to [
a
]
D
þ17.7 (c 1.9,
CHCl3) for the enantiomeric ester.15
3.3. (2S)-3-Trityloxy-2-methylpropan-1-ol, 15
We are currently in the process of comparing the biological
properties of enantio-N-TAC-iso-ADDA and enantio-N-TAC-ADDA’s
full biological profile as potential lead compounds for selective
phosphatase inhibition.
A solution of crude ester 14 (36.52 g, 0.10 mol) in anhydrous
diethyl ether (1100 mL), cooled down to ꢀ30 ꢁC, was cautiously
treated with small portions of solid lithium aluminium hydride
(6.09 g, 0.16 mol). The reaction mixture was then allowed to warm
up to room temperature, and the mixture was stirred overnight.
The mixture was quenched slowly and carefully by the addition of
water (6 mL), followed by a solution of sodium hydroxide (15 wt %,
6 mL). More water (18 mL) was then added, and the mixture was
stirred until a white precipitate formed. The mixture was filtrated
through Celite, and the solid was washed with ethyl acetate
(1000 mL) until no product remained in the solid as indicated by
TLC analysis. The organic filtrate was then dried over anhydrous
sodium sulfate, and the solvents were evaporated under reduced
pressure. Evaporation under high vacuum afforded the crude
product as an extremely viscous yellowish oil (37.46 g) that tends to
crystallise. Purification by flash chromatography (silica gel, 1% TEA,
20% ethyl acetate, 10% dichloromethane in 40–60 petroleum ether)
provided alcohol 15 as an extremely viscous and yellowish clear oil
(22.65 g, 67%), which can crystallise as a white powder after pro-
longed storage under high vacuum. Note: commercially available
solutions of LiAlH4 in diethyl ether can also be used with compa-
3. Experimental
3.1. General
All reactions were performed in oven-dried glassware under an
inert argon atmosphere unless otherwise stated. Tetrahydrofuran
(THF), diethyl ether and dichloromethane (DCM) were purified
through
a Pure Solv 400-5MD solvent purification system
(Innovative Technology, Inc). All reagents were used as-received,
unless otherwise stated. Solvents were evaporated under reduced
pressure at 40 ꢁC using a Buchi Rotavapor.
IR spectra were recorded as thin films on NaCl plates using
a JASCO FT/IR410 Fourier Transform spectrometer. Only significant
absorptions (nmax) are reported in wavenumbers (cmꢀ1).
Proton magnetic resonance spectra (1H NMR) and carbon
magnetic resonance spectra (13C NMR) were, respectively, recorded
at 400 MHz and 100 MHz using a Bruker DPX Avance400 in-
strument. Chemical shifts (
d
) are reported in parts per million
rable yields. The spectroscopic data were in full agreement with
26
(ppm) and are referenced to the residual solvent peak. The order of
citation in parentheses is (1) number of equivalent nuclei (by
integration), (2) multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, br¼broad, dm¼double multiplet) and (3)
coupling constant (J) quoted in hertz to the nearest 0.5 Hz.
High resolution mass spectra were recorded on a JEOL JMS-700
spectrometer by electrospray and chemical ionisation mass spec-
trometer operating at a resolution of 15,000 full widths at half
height.
that reported in the literature. [
a
]
ꢀ32.7 (c 1.0, CHCl3) compared
D
29
to [
a
]
D
þ28.4 (c 1.0, CHCl3) for the enantiomeric alcohol.16
3.4. (2E,4S)-Methyl 5-trityloxy-4-methylpent-2-enoate, 16
A ꢀ78 ꢁC solution of oxalyl chloride (414
mL, 4.89 mmol) in an-
hydrous dichloromethane (10 mL) was treated by the slow addition
of anhydrous dimethylsulfoxide (845 mL, 11.90 mmol), and the
mixture was stirred for 45 min under argon. A previously prepared
solution of alcohol 15 (797 mg, 2.40 mmol) in dry dichloromethane
(5 mL) was then added slowly at ꢀ78 ꢁC and the resulting mixture
was stirred for 1 h at ꢀ78 ꢁC. The reaction mixture was treated with
anhydrous diisopropylethylamine (1.50 mL, 8.61 mmol), and the
solution was stirred for a further 45 min at ꢀ78 ꢁC. The reaction
mixture was then poured into a separatory funnel containing acidic
water (20 mL H2Oþ7 mL 1.0 M HCl). The layers were separated, and
the organic fraction was washed with water (50 mL). The organic
phase was dried over anhydrous sodium sulfate, and concentrated
under vacuum to afford a very sticky yellowish oil (1.06 g), which
showed few impurities by 1H NMR spectroscopy. The crude was
then dissolved in dry dichloromethane and used immediately
without any further purification (50 mL, regular dichloromethane
was preferred when the reaction was carried out in larger scale).
Methyl(triphenylphosphoranylidene acetate) (1.76 g, 5.26 mmol)
was then added to the dichloromethane solution and the resulting
mixture was heated at reflux under argon for 3 days. The reaction
mixture was then cooled down to room temperature and worked
up by addition of enough 40–60 petroleum ether to force the tri-
phenylphosphine oxide to precipitate out. The solid was discarded
after filtration, and the process was repeated until no more tri-
phenylphosphine oxide could be forced out of solution. Subsequent
evaporation of the organic filtrates provided a very sticky orange oil
(930 mg), which was used without any further purification in the
next step. Purification by flash chromatography (silica gel, 1% TEA,
10% ethyl acetate in 40–60 petroleum ether) yielded an analytically
pure sample of the methyl ester 16 (835 mg, 90% over two steps) as
an extremely viscous colourless oil.
Flash chromatography was performed using silica gel (Apollo
Scientific Silica Gel 60, 40–63 mm) as the stationary phase. TLC was
performed on aluminium sheets pre-coated with silica (Merck
Silica Gel 60 F254). The plates were visualised by the quenching of
UV fluorescence (lmax 254 nm) and/or by staining with either
anisaldehyde, potassium permanganate, iodine or cerium ammo-
nium molybdate followed by heating.
3.2. (R)-(L)-3-Trityloxy-2-methylpropionate, 14
To a solution of methyl (R)-(ꢀ)-3-hydroxy-2-methylpropionate
13 (91 mg, 0.77 mmol) in anhydrous dichloromethane (5 mL) was
added anhydrous triethylamine (170 mL, 1.22 mmol) at room tem-
perature. After stirring the mixture at room temperature for 5 min,
the solution was cooled down to 0 ꢁC and a previously prepared
solution of tritylchloride (279 mg, 1.00 mmol) in dry dichloro-
methane (1 mL) was added slowly. The reaction mixture was then
allowed to warm up to room temperature and stirred overnight.
The reaction was then quenched by the addition of a saturated
solution of ammonium chloride (4 mL), and the mixture was
extracted with dichloromethane (2ꢂ5 mL). The combined organic
extracts were washed with brine (5 mL), dried over anhydrous
sodium sulfate and concentrated under vacuum to afford a sticky
yellowish oil (324 mg). Purification by flash chromatography (silica
gel, 1% TEA, elution gradient 0–20% ethyl acetate in petroleum
ether) yielded the pure trityl-protected ester 14 as a sticky, clear
and colourless oil (277 mg, 100%), which tended to form white
crystals upon storage. For multigram scale, the ester 14 was taken

S. Meiries et al. / Tetrahedron 65 (2009) 2951–2958
2955
24.5
1H NMR (400 MHz, CDCl3)
d
1.04 (3H, d, J¼6.8 Hz), 2.58 (1H,
91.5, 122.6, 126.8, 127.7, 128.7, 139.3, 144.2, 162.6; [
a]
ꢀ1.4
D
app sept, J¼6.8 Hz), 3.02 (1H, dd, J¼8.6, 6.3 Hz), 3.04 (1H, dd,
J¼8.8, 6.7 Hz), 3.69 (3H, s), 5.82 (1H, app dd, J¼15.8, 0.8 Hz), 6.92
(1H, dd, J¼15.8, 7.3 Hz), 7.17–7.41 (15H, m); 13C NMR (100 MHz,
(c 1.0, CHCl3); IR (thin film) nmax¼3342, 3087, 3059, 3023, 2961,
2926, 2871, 1661, 1490, 1448, 1307, 1290, 1218, 1073, 974, 797, 763,
707, 649 cmꢀ1
.
CDCl3)
151.9, 167.1; [
d 16.2, 37.2, 51.4, 67.1, 86.4, 120.4, 126.9, 127.7, 128.6, 144.0,
25
a]
ꢀ3.4 (c 1.0, CHCl3); IR (thin film) nmax¼3087,
3.7. 2,2,2-Trichloro-N-((3R,4S)-5-trityloxy-4-methylpent-1-
en-3-yl)acetamide, 19syn, and 2,2,2-trichloro-N-((3R,4R)-5-
trityloxy-4-methylpent-1-en-3-yl)acetamide, 19anti
D
3059, 3023, 2963, 2952, 2915, 2872, 1720, 1658, 1598, 1491, 1448,
1437, 1275, 1218, 1196, 1180, 1153, 1072, 1033, 983, 765, 707,
632 cmꢀ1
;
HRMS (EI) observed Mþ 386.1886, calculated for
C26H26O3 386.1882.
A solution of trichloroacetimidate 18 (9.84 g, 19.57 mmol) in
anhydrous dichloromethane (435 mL) was treated with p-benzo-
3.5. (4S,2E)-5-Trityloxy-4-methylpent-2-en-1-ol, 17
quinone
(3.12 g,
28.86 mmol)
and
bis(acetonitrile)di-
chloropalladium(II) (460 mg, 1.77 mmol, 9.1 mol %). The reaction
mixture was stirred at room temperature until TLC analysis
indicated completion (24 h). An initial filtration of the reaction
mixture through a short pad of silica was then used to remove the
main colouring agent. The silica pad was then flushed with diethyl
ether and the combined organic flushes were concentrated to
afford a crude residue that was purified by flash column chroma-
tography (silica gel, 1% TEA, 10% ethyl acetate in 40–60 petroleum
ether) to afford the desired terminal alkene 19 as a mixture of two
diastereoisomers (4:1, syn/anti) (8.71 g, 89%) as a very viscous and
clear light brown oil. The two diastereoisomers were separated
successfully by recrystallisation (ethanol/40–60 petroleum ether)
to afford 19syn as a white powder.
A 0 ꢁC solution of ester 16 (17.15 g, 44.40 mmol) in anhydrous
diethyl ether (1400 mL) was treated with the slow addition of
Dibal-H (1.0 M in hexanes, 121.0 mL, 0.121 mol). The resulting
mixture was then immediately removed off the cooling bath and
was allowed to warm up to room temperature where it was stirred
under argon until completion as indicated by TLC analysis (2 h). The
reaction was then quenched by the dropwise addition of water
(100 mL), followed by aq HCl (1.0 M, 10 mL). Ethyl acetate (500 mL)
was added to the mixture, and the two phases were separated. The
organic layer was subsequently washed with water (300 mL), acidic
water (250 mL of waterþ50 mL of HCl 1 M) and finally with water
(300 mL) one last time. The aqueous layers were then combined,
and extracted with ethyl acetate (300 mL). The combined organic
fractions were then dried over anhydrous sodium sulfate, and the
solvent was evaporated under vacuum to yield a crude sticky yel-
lowish oil residue (15.22 g). This crude oil was purified by flash
chromatography (silica gel, 1% TEA, 20% ethyl acetate, 10%
dichloromethane in 40–60 petroleum ether) to give the desired
allylic alcohol 17 (12.41 g, 78%, 100% ee) as a clear yellowish oil. The
enantiomeric excess was determined through Chiral HPLC analysis
with a Chiracel AD column using hexane/isopropanol (99:1) at
a flow rate of 0.75 mL/min.
3.7.1. One-pot procedure
To a 0 ꢁC solution of allylic alcohol 17 (812 mg, 2.27 mmol) in
anhydrous dichloromethane (50 mL) was added DBU (67
mL,
0.43 mmol) followed by trichloroacetonitrile (320 L, 3.19 mmol).
m
The reaction mixture was then allowed to warm up to room tem-
perature where it was stirred until completion as indicated by TLC
analysis (2 h). p-Benzoquinone (315 mg, 2.91 mmol) and bis(ace-
tonitrile)dichloropalladium(II) (63 mg, 0.24 mmol, 10.7 mol %)
were then quickly added into the reaction mixture at the same
time, and the reaction mixture was stirred under argon for 5 h. At
this time, extra p-benzoquinone (158 mg, 1.46 mmol)
and bis(acetonitrile)dichloropalladium(II) (47 mg, 0.18 mmol,
8.0 mol %) were added, and the reaction was stirred at room tem-
perature until completion as indicated by TLC analysis (2 days). The
reaction mixture was filtrated through a pad of silica gel and
flushed with diethyl ether. Evaporation under reduced pressure of
the organic solvent afforded a dark brown oil (1.46 g). Purification
of the oily residue by flash chromatography (silica gel, 1% TEA, 10%
ethyl acetate in 40–60 petroleum ether) gave the expected terminal
alkene 19 (1.08 g, 95% over two steps) as a viscous and clear light
brown oil. As in the two-pot procedure, the pure terminal alkene 19
was obtained as a 4:1 (syn/anti) mixture of diastereoisomers, which
could be separated by recrystallisation to afford 19syn as a white
powder (ethanol/40–60 petroleum ether).
1H NMR (400 MHz, CDCl3)
d
1.07 (3H, d, J¼6.8 Hz),1.26 (1H, br s),
2.50 (1H, app sept, J¼6.4 Hz), 2.95 (1H, dd, J¼8.7, 6.7 Hz), 3.03 (1H,
dd, J¼8.7, 6.4 Hz), 4.09 (2H, br s), 5.64–5.66 (2H, m), 7.21–7.46
(15H, m); 13C NMR (100 MHz, CDCl3)
d 17.1, 36.9, 63.7, 68.0, 86.2,
23
126.8, 127.6, 128.5, 128.7, 135.6, 144.2; [
(thin film) nmax¼3580, 3375, 3087, 3059, 3022, 2961, 2952, 2913,
2870, 1597, 1491, 1448, 1218, 1071, 973, 753, 707, 633 cmꢀ1
a]
þ3.6 (c 1.0, CHCl3); IR
D
.
3.6. (4S,2E)-5-Trityloxy-4-methylpent-2-enyl-2,2,2-
trichloroacetimidate, 18
To a ꢀ78 ꢁC solution of allylic alcohol 17 (73 mg, 0.204 mmol)
in anhydrous dichloromethane (5 mL) were added tri-
chloroacetonitrile (30 mL, 0.30 mmol) and DBU (6.2 mL, 0.04 mmol).
The mixture was slowly allowed to warm up to room temperature,
where it was stirred under argon until completion as indicated
by TLC analysis (3 h). The reaction was quenched by addition of
water (5 mL), and diluted with diethyl ether (20 mL). The phases
were separated, and the aqueous layer was extracted with ethyl
acetate (20 mL). The organic extracts were combined, and dried
over sodium sulfate before being concentrated under vacuum to
afford a crude yellowish oil (121 mg). Purification of oily residue
by flash column chromatography (silica gel, 1% TEA, elution
gradient 0–5% ethyl acetate in 40–60 petroleum ether) afforded
the desired trichloroacetimidate 18 (99 mg, 97%) as a sticky
colourless oil.
Compound 19syn. 1H NMR (400 MHz, CDCl3)
d 0.82 (3H, d,
J¼7.2 Hz), 2.12 (1H, m), 3.12 (1H, t, J¼9.8 Hz), 3.26 (1H, dd, J¼10.0,
4.0 Hz), 4.38–4.46 (1H, m), 5.12 (1H, app dt, J¼10.4,1.2 Hz), 5.14 (1H,
app dt, J¼17.1, 1.3 Hz), 5.52 (1H, ddd, J¼17.0, 10.4, 6.1 Hz), 7.23–7.45
(15H, m), 7.76 (1H, d, J¼8.1 Hz); 13C NMR (100 MHz, CDCl3)
d 14.4,
36.7, 57.2, 65.9, 87.9, 92.8, 117.8, 127.2, 127.9, 128.7, 132.4, 143.3,
24
161.1; [
a]
ꢀ1.6 (c 1.0, CHCl3); IR (thin film) nmax¼3368, 3086, 3058,
D
3022, 2967, 2927, 2883, 1706, 1492, 1448, 1218, 1036, 821, 759, 707,
633 cmꢀ1. Mp 140 ꢁC.
Compound 19anti. 1H NMR (400 MHz, CDCl3)
d 1.24 (3H, d,
J¼7.1 Hz), 2.00 (1H, m), 3.12 (1H, t, J¼9.8 Hz), 3.26 (1H, dd, J¼10.0,
4.0 Hz), 4.39–4.45 (1H, m), 4.98 (1H, br d, J¼10.2 Hz), 5.01 (1H, d,
J¼17.0 Hz), 5.49 (1H, partially masked dd, J¼17.0, 10.2 Hz), 7.23–
7.46 (15H, m), 7.59 (1H, d, J¼7.7 Hz); 13C NMR (100 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
d
1.06 (3H, d, J¼6.8 Hz), 2.53 (1H,
app sept, J¼6.5 Hz), 2.99 (1H, dd, J¼8.7, 6.2 Hz), 3.03 (1H, dd,
J¼8.7, 6.7 Hz), 4.78 (2H, d, J¼6.1 Hz), 5.72 (1H, dtd, J¼15.6, 6.1,
0.9 Hz), 5.88 (1H, br dd, J¼15.6, 7.0 Hz), 7.21–7.46 (15H, m), 8.29
d
14.9, 36.8, 57.5, 64.2, 87.4, 92.7, 116.0, 127.1, 127.9, 128.7, 135.0,
(1H, s); 13C NMR (100 MHz, CDCl3)
d
16.8, 37.1, 67.8, 69.9, 86.2,
143.2, 161.7.

2956
S. Meiries et al. / Tetrahedron 65 (2009) 2951–2958
3.8. 2,2,2-Trichloro-N-((3R,4S)-5-hydroxy-4-methylpent-
NMR (100 MHz, CDCl3) d 13.3, 42.5, 55.3, 92.6, 119.4, 131.9, 161.2,
1-en-3-yl)acetamide, 20
178.8; IR (thin film) nmax¼3411, 3344, 3201, 3088, 3021, 2986, 2927,
2855, 2651, 2552, 1709, 1510, 1265, 1216, 823, 755, 668 cmꢀ1. HRMS
(CI) observed (MþH)þ 273.9794, calculated for C8H11O3NCl3
273.9805.
A
solution of trityl-protected alcohol 19syn (545 mg,
1.08 mmol) in dichloromethane (5 mL) was treated by the slow
addition of a commercially available solution of HCl in anhydrous
diethyl ether (1.0 M, 2.0 mL, 2.0 mmol) at room temperature. The
reaction mixture was stirred for 1 h, and was then concentrated
under vacuum without any prior work up. The crude viscous oil
(550 mg) was purified by flash chromatography (silica gel, elution
gradient 5–10% ethyl acetate in 40–60 petroleum ether) to give the
desired alcohol 20 (281 mg, 100%) as a very viscous, clear and
colourless oil.
Compound 21anti. 1H NMR (400 MHz, CDCl3)
d 1.35 (3H, d,
J¼7.3 Hz), 2.87 (1H, m), 4.56 (1H, m), 5.19 (1H, br dd, J¼10.5, 1.2 Hz),
5.24 (1H, dd, J¼15.9,1.2 Hz), 7.77 (1H, ddd, J¼15.9,10.5, 5.3 Hz), 8.32
(1H, v br s); 13C NMR (100 MHz, CDCl3)
134.3, 161.9, 180.0.
d 15.0, 42.6, 54.9, 91.9, 117.5,
3.10. (2S,3R)-Methyl 2-methyl-3-(2,2,2-trichloroacetamido)
pent-4-enoate, 22, and (2R,3R)-methyl 2-methyl-3-
(2,2,2-trichloroacetamido)pent-4-enoate, 23
1H NMR (400 MHz, CDCl3)
d
0.86 (3H, d, J¼7.1 Hz), 2.18 (1H,
m), 2.28 (1H, dd, J¼5.5, 4.7 Hz), 3.53 (1H, app td, J¼10.6, 4.6 Hz),
3.65 (1H, m), 4.58–4.64 (1H, m), 5.28 (1H, dm, J¼17.2 Hz), 5.28
(1H, dm, J¼10.6 Hz), 5.86 (1H, ddd, J¼17.1, 10.7, 5.4 Hz), 7.80 (1H,
A solution of the acid diastereoisomeric mixture 21syn and
21anti (210 mg, 0.76 mmol) in anhydrous diethyl ether (4.5 mL) was
treated with the dropwise addition of a commercial solution of TMS-
diazomethane in hexanes (0.8 mL, 2.0 M, 1.6 mmol). The resulting
yellow solution was stirred overnight, and was subsequently
quenched by the sequential and careful addition of acetic acid
br s); 13C NMR (100 MHz, CDCl3)
d 12.3, 38.6, 55.7, 65.1, 92.8,
24
117.3, 133.4, 161.8; [
a
]
þ15.6 (c 1.0, CHCl3); IR (thin film)
D
nmax¼3468, 3427, 3321, 3085, 3017, 2966, 2934, 2882, 1698, 1644,
1516, 1241, 1036, 994, 928, 823, 757, 735, 683, 666 cmꢀ1; HRMS
(CI) observed (MþH)þ 260.0007, calculated for C8H13O2NCl3
260.0012.
(180 mL, 2.62 mmol) and potassium fluoride (50 mg, 0.86 mmol).
After the mixture was stirred for 10 min, the solution was treated
with aq HCl (1.0 M, 2ꢂ10 mL). The layers were separated and the
organic phase was dried over anhydrous magnesium sulfate, and the
solvent was evaporated under reduced pressure to afford the crude
esters (359 mg) as a yellow oil. Purification by flash column chro-
matography (silica gel, elution gradient 0–10% ethyl acetate in 40–60
petroleum ether) provided the desired methyl esters 22 and 23 as
aviscous, clear oil and as an inseparable mixture (60 mg, 27%) of syn/
anti (5:3) diasteromers. The TMS-methyl esters 24syn and 24anti
(115 mg, 42%, d.r. 5:3) werealso isolated as an inseparable mixture of
diastereomers.
The diastereomeric mixture was then loaded onto a semi-
preparative HPLC under reverse phase conditions as a MeCN/H2O
(50:50) stock solution (C18 column). The separation was achieved
using the following elution profile: initial elution gradient in-
creased the acetonitrile concentration from 25% to 45% over 20 min.
The concentration was kept at 45% for 55 min and was then
increased from 45% to 95% over 5 min. Finally, the concentration
was kept at 95% for an additional 10 min at which point the run was
terminated. Methyl ester 22 was isolated after 52.85 min. Methyl
ester 23 was isolated after 55.90 min. Finally, the enriched fraction
containing TMS-methylene ester 24syn was isolated after
68.48 min (syn/anti 7.5:1.0). In all cases, the optimised detection
wavelength was 214 nm.
3.9. (2R,3R)-2-Methyl-3-(2,2,2-trichloroacetamido)pent-4-
enoic acid, 21syn, and (2R,3R)-2-methyl-3-(2,2,2-
trichloroacetamido)pent-4-enoic acid, 21anti
A ꢀ78 ꢁC solution of oxalyl chloride (113
mL, 1.34 mmol) in
anhydrous dichloromethane (12 mL) was treated by the slow ad-
dition of anhydrous dimethylsulfoxide (191 mL, 2.69 mmol), and
the resulting mixture was stirred at ꢀ78 ꢁC for 45 min. A pre-
viously prepared solution of alcohol 20 (210 mg, 0.806 mmol) in
dry dichloromethane (6 mL) was then slowly added and the re-
action mixture was stirred for a further 1 h at ꢀ78 ꢁC. The reaction
mixture was treated with anhydrous triethylamine (521 mL,
3.74 mmol), and the reaction mixture was allowed to warm up to
room temperature and stirred for a further 1 h. The reaction was
quenched by addition of water (10 mL), and the phases were
separated. The organic layer was washed with water (2ꢂ10 mL)
and the combined aqueous fractions were extracted with ethyl
acetate (10 mL). The combined organic extracts were dried over
anhydrous sodium sulfate and concentrated under vacuum to af-
ford the crude aldehyde (237 mg) as a viscous orange oil, and as
a 5:3 mixture of (syn/anti) diastereomers. The crude aldehyde was
solubilised in tert-butanol (4.5 mL) and 2-methyl-2-butene
(695 mL, 6.56 mmol) was added. This resulting solution was then
treated slowly with a freshly made aqueous solution of sodium
chlorite (555 mg, 6.14 mmol) and sodium phosphate monobasic
dihydrate (816 mg, 5.23 mmol) in water (2.2 mL total volume) at
room temperature. The reaction mixture was stirred overnight at
room temperature and subsequently quenched by the dropwise
addition of concd HCl (0.2 mL). The acidic mixture was then
extracted with ethyl acetate (3ꢂ15 mL) and dichloromethane
(30 mL). The combined organic extracts were dried over magne-
sium sulfate, and the solvent was removed under reduced pres-
sure to give the crude acid mixture 21syn/anti (545 mg) as
a viscous yellow oil. Purification by flash chromatography (silica
gel, 20% ethyl acetate in 40–60 petroleum ether) afforded the
carboxylic acids 21syn and 21anti (213 mg, 96%) as an inseparable
mixture of diastereomers (syn/anti, 5:3) as a viscous, clear and
colourless oil.
3.10.1. (2S,3R)-Methyl 2-methyl-3-(2,2,2-trichloroacetamido)
pent-4-enoate, 22
1H NMR (400 MHz, CDCl3)
d
1.21 (3H, d, J¼7.3 Hz), 2.84 (1H, qd,
J¼7.3, 4.7 Hz), 3.70 (3H, s), 4.49–4.53 (1H, m), 5.26 (1H, app dt,
J¼10.3, 1.0 Hz), 5.28 (1H, app dt, J¼17.1, 1.0 Hz), 5.77 (1H,
ddd, J¼17.0, 10.3, 6.6 Hz), 7.71 (1H, br d, J¼7.2 Hz); 13C NMR
(100 MHz, CDCl3)
d 13.4, 42.5, 52.1, 55.5, 92.6, 118.9, 132.2, 160.9,
24
173.8; [
a
]
þ65.6 (c 1.0, CHCl3); IR (thin film) nmax¼3419, 3029,
D
2965, 2926, 2870, 1496, 1454, 1038, 742, 700 cmꢀ1; HRMS (ESI)
observed (MþH)þ 287.9956, calculated for C9H13O3NCl3 287.9955.
3.10.2. (2R,3R)-Methyl 2-methyl-3-(2,2,2-trichloroacetamido)
pent-4-enoate, 23
1H NMR (400 MHz, CDCl3)
d
1.30 (3H, d, J¼7.2 Hz), 2.84 (1H, qd,
J¼7.2, 3.8 Hz), 3.71 (3H, s), 4.52–4.57 (1H, m), 5.20 (1H, ddd, J¼10.5,
Compound 21syn. 1H NMR (400 MHz, CDCl3)
d 1.27 (3H,
1.5, 0.5 Hz), 5.27 (1H, ddd, J¼17.2, 1.6, 0.5 Hz), 5.80 (1H, ddd, J¼17.2,
d, J¼7.3 Hz), 2.87–2.94 (1H, m), 4.55–4.62 (1H, m), 5.33 (1H, app dt,
J¼10.3, 0.9 Hz), 5.35 (1H, app dt, J¼17.1, 1.0 Hz), 5.84 (1H, ddd,
J¼17.0, 10.3, 6.6 Hz), 7.59 (1H, br d, J¼8.0 Hz), 8.32 (1H, v br s); 13C
10.5, 5.2 Hz), 8.02 (1H, br d, J¼5.6 Hz); 13C NMR (100 MHz, CDCl3)
24
d
15.3, 42.4, 52.1, 55.2, 92.8, 116.9, 134.7, 161.9, 175.7; [
a]
þ26.8
D
(c 1.0, CHCl3).

S. Meiries et al. / Tetrahedron 65 (2009) 2951–2958
2957
3.10.3. (2S,3R)-(Trimethylsilyl)methyl-2-methyl-3-(2,2,2-
trichloroacetamido)pent-4-enoate, 24syn
a polished glass pipette to a solution of the crude carboxylic acid
21syn (299 mg) in diethyl ether (6 mL) at room temperature in an
open air round bottom flask. The yellow solution was then stirred
until completion as indicated by TLC analysis (30 min), and was
subsequently quenched by the careful dropwise addition of acetic
1H NMR (400 MHz, CDCl3)
d
0.07 (9H, s), 1.23 (3H, d, J¼7.3 Hz),
2.84 (1H, qd, J¼7.3, 4.6 Hz), 3.77 (1H, d, J¼14.1 Hz), 3.88 (1H, d,
J¼14.1 Hz), 4.47–4.55 (1H, m), 5.28 (1H, app dt, J¼10.4, 1.0 Hz), 5.31
(1H, app dt, J¼17.2, 1.0 Hz), 5.79 (1H, ddd, J¼17.1, 10.4, 6.7 Hz), 7.85
acid (150 mL, 2.62 mmol). After stirring the acidic mixture for
(1H, br d, J¼7.4 Hz); 13C NMR (100 MHz, CDCl3)
d
ꢀ3.1, 13.8, 42.7,
30 min, the solvent was evaporated under reduced pressure to give
the crude methyl ester 22 (359 mg) as a viscous yellow oil. Purifi-
cation by flash column chromatography (silica gel, elution gradient
0–10% ethyl acetate in 40–60 petroleum ether) provided the pure
methyl ester 22 as a single diastereomer (180 mg, 69% over three
steps) and as a colourless viscous oil.
24
55.8, 58.6, 92.7, 119.1, 132.2, 161.0, 174.3. [a]
D
þ41.9 (c 1.0, CHCl3)
enriched fraction (syn/anti 7.5:1.0).
3.10.4. (2R,3R)-(Trimethylsilyl)methyl-2-methyl-3-(2,2,2-
trichloroacetamido)pent-4-enoate, 24anti
1H NMR (400 MHz, CDCl3)
d
0.06 (9H, s), 1.29 (3H, d, J¼7.2 Hz),
1H NMR (400 MHz, CDCl3)
d
1.21 (3H, d, J¼7.3 Hz), 2.84 (1H,
2.84 (1H, qd, J¼7.2, 3.8 Hz), 3.81 (1H, s), 3.82 (1H, s), 4.47–4.55 (1H,
m), 5.20 (1H, ddd, J¼10.4, 1.5, 0.6 Hz), 5.26 (1H, ddd, J¼17.1, 1.5,
0.6 Hz), 5.79 (1H, ddd, J¼17.1, 10.4 Hz, one unresolved coupling),
qd, J¼7.3, 4.7 Hz), 3.70 (3H, s), 4.49–4.53 (1H, m), 5.26 (1H, app dt,
J¼10.3, 1.0 Hz), 5.28 (1H, app dt, J¼17.1, 1.0 Hz), 5.77 (1H, ddd,
J¼17.0, 10.3, 6.6 Hz), 7.71 (1H, br d, J¼7.2 Hz); 13C NMR (100 MHz,
24
8.14 (1H, br d, J¼8.2 Hz); 13C NMR (100 MHz, CDCl3)
d
ꢀ3.1, 15.5,
CDCl3) d 13.4, 42.5, 52.1, 55.5, 92.6, 118.9, 132.2, 160.9, 173.8; [a]
D
42.5, 55.2, 58.6, 92.8, 116.8, 134.9, 162.0, 175.6. IR (thin film)
nmax¼3340, 2958, 1718, 1509, 1298, 1252, 1180, 1154, 843, 822,
681 cmꢀ1; HRMS (FABþ) observed (MþH)þ 360.0355, calculated for
C12H21O3NCl3Si 360.0356.
þ65.6 (c 1.0, CHCl3); IR (thin film) nmax¼3419, 3029, 2965, 2926,
2870, 1496, 1454, 1038, 742, 700 cmꢀ1; HRMS (ESI) observed
(MþH)þ 287.9956, calculated for C9H13O3NCl3 287.9955.
3.11. (2S,3R,4E,6E,8R,9R)-Methyl 9-methoxy-2,6,8-trimethyl-
10-phenyl-3-(2,2,2-trichloroacetamido)deca-4,6-dienoate
(enantio-N-TAC-iso-ADDA methyl ester), 27, and
(2R,3R,4E,6E,8R,9R)-methyl 9-methoxy-2,6,8-trimethyl-10-
phenyl-3-(2,2,2-trichloroacetamido)deca-4,6-dienoate
(enantio-N-TAC-ADDA methyl ester), 28
3.10.5. (2S,3R)-Methyl 2-methyl-3-(2,2,2-trichloroacetamido)
pent-4-enoate, 22
A ꢀ78 ꢁC solution of oxalyl chloride (156
m
L, 1.84 mmol) in an-
hydrous dichloromethane (3 mL) was treated with dimethylsulf-
oxide (317
m
L, 4.46 mmol) and the mixture was stirred at ꢀ78 ꢁC for
45 min. A previously prepared solution of alcohol 20 (235 mg,
0.902 mmol) in dry dichloromethane (2 mL) was then added slowly
and the resulting mixture was stirred at ꢀ78 ꢁC for a further 1 h.
The reaction mixture was then treated slowly with anhydrous
3.11.1. General procedure
Neat methoxy diene 910c (140 mg, 0.608 mmol) and the di-
astereomeric mixture of methyl esters 22 and 23 (263 mg,
0.91 mmol) were placed in a round bottom flask equipped with
a reflux condenser and wrapped up in aluminium foil. Second
generation Hoveyda–Grubbs catalyst 26 (40 mg, 0.06 mmol,
7.0 mol %) was then quickly introduced to the reaction mixture
followed by the fast addition of anhydrous tetrahydrofuran (20 mL).
The mixture was then immediately placed in an oil bath pre-heated
at 110 ꢁC, and the reaction mixture was heated at reflux under
argon until completion as indicated by TLC analysis (24 h). The
reaction mixture was cooled down to room temperature, and it was
diluted with hexanes (30 mL), which caused the catalyst derivatives
to crash out of solution. Filtration of the solid residue followed by
concentration of the remaining organic solvent under reduced
pressure afforded a crude light brown oil. Note: when dealing with
microscale amounts, a better work-up procedure involves the
simple evaporation of the solvent under vacuum followed by
purification of the crude residue.
DIPEA (550 mL, 3.16 mmol) and the reaction mixture was stirred for
an extra 45 min at ꢀ78 ꢁC. The reaction mixture was then poured
into an extraction funnel containing acidic water (8 mL
H2Oþ2.6 mL 1.0 M HCl). The phases were separated, and the
organic fraction was washed with water (20 mL) one more time.
The organic layer was dried over anhydrous sodium sulfate and
concentrated under vacuum to afford the desired aldehyde
intermediate 25 as a viscous yellowish oil (311 mg).
1H NMR (400 MHz, CDCl3)
d
1.22 (3H, d, J¼7.5 Hz), 2.78 (1H, qd,
J¼7.4, 4.2 Hz), 4.61–4.66 (1H, m), 5.25–5.30 (2H, m), 5.82 (1H, ddd,
J¼17.10, 10.3, 6.7 Hz), 7.41 (1H, br d, J¼8.9 Hz), 9.66 (1H, s); 13C NMR
(100 MHz, CDCl3)
d 10.4, 48.9, 54.4, 92.4, 119.1, 132.6, 161.1, 203.4.
The crude aldehyde 25 was dissolved in tert-butanol (5.0 mL)
and 2-methyl-2-butene (773 L, 7.30 mmol) was added to the so-
m
lution. The mixture was then slowly treated with a freshly made
aqueous solution of sodium chlorite (621 mg, 6.87 mg) and sodium
phosphate monobasic dehydrate (913 mg, 5.85 mmol) in water
(2.5 mL) at room temperature. The reaction mixture was stirred
until completion as indicated by TLC analysis (1 h) and was then
The crude oil was purified by flash column chromatography
(silica gel, elution gradient 0–10% ethyl acetate in 40–60 petroleum
ether) to afford the heterodimers 27 and 28 as a light brown and
very sticky clear oil. A second purification by flash column chro-
matography (silica gel, 100% toluene) was necessary to give the
analytically pure heterodimers 27 and 28 (269 mg, 90%) as an
inseparable 5:3 mixture of diastereomers.
The same procedure was repeated for the successful cross-
coupling of each individual diastereomerically pure esters 22
and 23.
quenched by the dropwise addition of concd HCl (220 mL). Water
(10 mL) was then added to the solution, and the aqueous layer was
extracted with ethyl acetate (2ꢂ10 mL). The organic fractions were
combined and were dried over magnesium sulfate before being
evaporated under reduced pressure to give the crude acid 21syn
(299 mg) as a very viscous yellow oil.
1H NMR (400 MHz, CDCl3)
d
1.23 (3H, d, J¼7.3 Hz), 2.87 (1H, qd,
J¼7.2, 4.8 Hz), 4.55–4.62 (1H, m), 5.27 (1H, app dt, J¼10.3, 0.9 Hz),
5.30 (1H, app dt, J¼17.1, 1.0 Hz), 5.80 (1H, ddd, J¼17.0, 10.4, 6.6 Hz),
7.72 (1H, br d, J¼8.9 Hz), 9.40 (1H, v br s).
3.11.2. enantio-N-TAC-iso-ADDA methyl ester, 27
1H NMR (400 MHz, CDCl3)
d
1.03 (3H, d, J¼6.8 Hz), 1.23 (3H, d,
A 0 ꢁC 3 M aq solution of sodium hydroxide (12.7 mL) topped up
with diethyl ether (19 mL) was carefully treated by the addition of
small portions of a suspension of N-methyl-N0-nitro-N-nitro-
soguanidine (MNNG) (1.0 g in total, 50% in water, 3.40 mmol). After
the bubbling has ceased (10 min), the yellow ethereal solution of
diazomethane was transferred slowly and carefully using
J¼7.3 Hz), 1.62 (3H, d, J¼1.2 Hz), 2.56–2.65 (1H, m), 2.68 (1H, dd,
J¼13.9, 7.4 Hz), 2.79 (1H, dd, J¼13.9, 4.6 Hz), 2.88 (1H, qd, J¼7.2,
4.5 Hz), 3.20 (1H, m), 3.24 (3H, s), 3.73 (3H, s), 4.57 (1H, app tm,
J¼7.9 Hz), 5.42 (1H, dd, J¼15.3, 7.5 Hz), 5.43 (1H, d, J¼10.6 Hz), 6.28
(1H, d, J¼15.6 Hz), 7.17–7.29 (5H, m), 7.72 (1H, d, J¼8.8 Hz); 13C
NMR (100 MHz, CDCl3)
d 12.7, 13.7, 16.1, 37.7, 38.2, 43.0, 52.1, 55.7,

2958
S. Meiries et al. / Tetrahedron 65 (2009) 2951–2958
5. Blom, J. F.; Juttner, F. Toxicon 2005, 46, 465.
58.6, 86.8, 92.8, 120.3, 126.0, 128.2, 129.4, 132.2, 137.4, 139.3, 139.7,
24
6. Rinehart, K. L.; Namikoshi, M.; Choi, B. Y. J. Appl. Phycol. 1994, 6, 159.
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160.8, 174.2; [
a
]
þ12.4 (c 1.0, CHCl3); IR (thin film) nmax¼3408,
D
3356, 3029, 2980, 2953, 2935, 2879, 1718, 1509, 1456, 1266, 1200,
822, 739, 702 cmꢀ1; HRMS (ESI) observed (MþH)þ 490.1313, cal-
culated for C23H31O4NCl3 490.1313.
3.11.3. enantio-N-TAC-ADDA methyl ester, 28
1H NMR (400 MHz, CDCl3)
d
1.03 (3H, d, J¼6.8 Hz), 1.30 (3H, d,
J¼7.2 Hz), 1.60 (3H, d, J¼0.9 Hz), 2.55–2.63 (1H, m), 2.67 (1H, dd,
J¼13.9, 7.5 Hz), 2.79 (1H, dd, J¼13.9, 4.6 Hz), 2.86 (1H, qd, J¼7.2,
4.0 Hz), 3.16–3.22 (1H, m), 3.23 (3H, s), 3.72 (3H, s), 4.53–4.62 (1H,
m), 5.41 (1H, d, J¼9.5 Hz), 5.44 (1H, dd, J¼15.8, 6.5 Hz), 6.24 (1H, d,
J¼15.6 Hz), 7.17–7.29 (5H, m), 8.01 (1H, d, J¼9.0 Hz); 13C NMR
(100 MHz, CDCl3)
d 12.7, 15.3, 16.1, 36.7, 38.2, 43.3, 52.1, 55.3, 58.7,
86.9, 92.9, 122.9, 126.0, 128.2, 129.4, 132.1, 137.2, 137.6, 139.3, 161.7,
24
175.9; [
a
]
þ11.2 (c 1.0, CHCl3).
D
Acknowledgements
11. (a) Jung, M. E.; D’Amico, D. C. J. Am. Chem. Soc. 1993, 115, 12208; (b) Jung, M. E.;
D’Amico, D. C. J. Am. Chem. Soc. 1997, 119, 12150; (c) Jung, M. E.; Lee, W. S.;
Sun, D. Org. Lett. 1999, 1, 307; (d) Jung, M. E.; Marquez, R. Org. Lett. 2000, 2, 1669.
12. (a) Overman, L. E.; Carpenter, N. E. Org. React. 2005, 66, 1; (b) Calter, M.; Hollis,
T. K.; Overman, L. E.; Ziller, J.; Zipp, G. G. J. Org. Chem. 1997, 62, 1449; (c)
Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597; (d) Overman, L. E. J. Am. Chem.
Soc. 1976, 98, 2901; (e) Overman, L. E.; Hollis, T. K. Tetrahedron Lett. 1997, 38,
8837; (f) Anderson, C. E.; Donde, Y.; Douglas, C. J.; Overman, L. E. J. Org. Chem.
2005, 70, 648; (g) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003, 125,
12412; (h) Overman, L. E.; Owen, C. E.; Pavan, M. M.; Richards, C. J. Org. Lett.
2003, 5, 1809; (i) Kirsh, S. F.; Overman, L. E.; Watson, M. P. J. Org. Chem. 2004, 69,
8101.
13. The atomic coordinates for 19syn (CCDC deposition number CCDC699929) are
available upon request from the Cambridge Crystallographic Centre, University
Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
The crystallographic numbering system differs from that used in the text;
therefore, any request should be accompanied by the full literature citation of
this paper.
S.M. would like to thank the EPSRC for a postgraduate stu-
dentship. R.M. is grateful to Dr. Ian Sword, the EPSRC, and the
University of Glasgow for financial support. We would also like to
acknowledge Dr. Verena Bo¨hrsch and Dr. Richard Hartley for useful
discussions.
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